21-fluoro-delta-pregnene-17alpha-ol-3, 20-dione



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Patent @iiiee 3,050,536 21-FLUGR0-A -PREGNENE-17Ot-OL-3,20-DHONE JosefFried, Princeton, Ni, and Josef E. Hera, Lornas,

Mexico City, Mexico, assignors to (Blin Mathieson Chemical Corporation,New York, N.Y., a corporation of Virginia No Drawing. Filed May 8, 1961,Ser. No. 108,309 1 Claim. (Cl. 260-39747) This application is acontinuation-in-part of our copending application Serial No. 599,310,filed July 23, 1956, now abandoned.

This invention relates to the synthesis of steroids and has for itsobjects the provision of (I) an advantageous process of preparing thenew steroid: 21-iiuoro-A -pregnene-17a-ol-3,20-dione; and (II) said newsteroid, which is useful in itself as a physiologically active steroid.

The process of this invention essentially comprises interacting a21-alkanesulfonic acid ester of Reichsteins Compound S [A-pregnene-17a,21-dio1-3,20-dione] or the corresponding 21-chloro, bromoor iodo derivative (e.g., 2l-chloro-Mpregnene-l7a-ol-3,20-dione) withpotassium fluoride to form 21-fluoro-A -pregnene-17a-ol-3,20-dione.

Suitable starting materials utilizable in the process of this inventioninclude the 2l-alkanesulfonic acid esters (particularly the lower.alkanesulfonic acid esters, as exemplified by the methanesulfonic acidester) of Compound S, 2l-chloro-n -pregnene-l7a-ol-3,20-dione, 21-bromo-A -pregnene-17a-ol-3,20-dione and 21-iodo-Apregnene-17a-ol-3,20-dione. In accordance with the process of thisinvention, one of these starting materials is interacted with potassiumfluoride. This reaction is preferably conducted in an organic solvent ofhigh dielectric constant, such as dimethylformamide, dimethylsulfoxide,and diethylene glycol, optimally at an elevated temperature, such as onein the range of about 100 C. to about 130 C.

The 2l-fluoro-A -pregnene-17a-ol-3,20-dione steroid of this invention isa physiologically active steroid which possesses mineralocorticoidactivity. Thus, the new steroid can be administered instead of, and inthe same manner as, desoxycorticosterone in the treatment of Addisonsdisease. The dosage for such administration is, of course, dependent onthe relative activity of the compound. The mineralocorticoid activity of2l-fluoro- A -pregnene-17a-ol-3,20-dione is in distinct contrast toanalogous compounds. At a minimum dose of 0.25 mg, the 21-fiuorocompound causes increased retention of sodium. In contrast, 2.5 mg. ofthe analogous 2l-chloro compound are required to elicit a minimumresponse in the sodium retention assay. The 21-bromo compound shows noresponse at 2.5 mg. Only the 21-fluoro compound shows increasedpotassium excretion at 2.5 mg.; neither the chloro nor bromo compoundshows any potassium response at this dose level.

The following example is illustrative of the invention (all temperaturesbeing in centigrade):

EXAMPLE 21-Flu0r0-A -Pregnene-17a-0l-3,20-Dione and A -Pregnene-I7a,21-0xid0-3,20-Di0ne From M-Pregnene-l 7a, 12-Di0l-3,20-Di0ne (a)PREPARATION OF A -PREGNENE-17a,21-DIOL-3,20- DIONE 21l\IESYLATE To asolution of 2.0 g. of A -pregnene-17a,21-diol-3,20- dione in 24 ml. ofanhydrous pyridine is added at 1.05 ml. of methanesulfonyl chloride, andthe mixture is allowed to remain at 0 for 2.5 hours. Ice water is addedcarefully and the resulting crystalline precipitate filtered off andwashed with water. The crude precipitate (about 2.36 g.) afterrecrystallization from 95% alcohol has the following properties: M1about 181-183 (dec.); [(11 +123 (c., 0.58 in chloroform).

A.-'talysi.s'.-Calcd. for C H O S (424.48): C, 62.25; H, 7.60; S, 7.46.Found: C, 61.79; H, 7.13; S, 7.40.

(b) REACTION OF THE MESYLATE WITH POTASSIUM FLUORIDE A solution of 1.2g. of the mesylate prepared in part (a) and 1.2 g. of anhydrouspotassium fluoride in ml. of dimethylsulfoxide is heated with stirringat 110 for 18 hours. The mixture is diluted with Water and the steroidextracted with ethyl acetate. The ethyl acetate extract is Washed withwater, dried over sodium sulfate and evaporated to dryness in vacuo. Theresidue on direct crystallization from acetone yields about 110 mg. ofthe 21-fluoroA -pregnene-17a-ol-3,20-dione, having the followingproperties: M.P. about 224226 and 233- 235 (dimorphic); [ch (c., 0.34 inCHCIg);

mg, 240 ma (6 =16,800); W 2.94, 5.79, 5.99, 6.19M

Analysis.Calcd. for (3 1-1 0 1 (348.44): C, 72.38; H, 8.39; F, 5.45.Found: C, 72.37; H, 8.52; F, 5.50.

The combined mother liquor material is dissolved in 40 ml. of benzeneand 20 ml. of hexane and chromatographed on 20 g. of sulfuric acidwashed alumina. A mixture of benzene-hexane 2:1 (2000 m1.) elutes about245 mg. of A -pregnene-17c,21-oxido-3,20-dione, which afterrecrystallization from acetone has the following properties: M.P. about199201; [ch +213 (c., 0.61 in CHCl reg-L 239 m (16,600) A222 No OHbands, 5.51; 6.00, 6.20;;

Analysis.-Calcd. for C21I'I2803 (328.43): C, 76.79; H, 8.59. Found: C,76.72; H, 8.51.

Subsequent elution of the column with 10% chloroform in benzene anadditional amount (about 300 mg.) of 21 -fiuoro-A-pregnene-17a-ol-3,20-dione.

(c) REARRANGEMENT OF A PREGNENE -I'Ya,21-OXIDO- TO AIS-NORPREGNENEJSa,21-OXIDO-3,20-

max.

Armlysis.-Calcd. for C H O (328.44): C, 76.79; H, 8.59. Found: C, 76.77;H, 8.59.

Reported in the literature [Allen et al., J. Am. Chem. Soc., 77, 4784(1955)]: M.P. 224226; [m] +92; REE? 5.70 1, 6.00p., 6.1911.

The invention may be otherwise variously embodied within the scope ofthe appended claim.

We claim:

21fiuoro-A -pregnene-17aol-3,20-dione.

References Cited in the file of this patent UNITED STATES PATENTS2,668,816 Miescher et a1 Feb. 9, 1954 FOREIGN PATENTS 717,130 GreatBritain Oct. 20, 1954

